Drug is approved for its manufacture and distribution only after its quality is warranted. In Japan, that is stipulated in Article 14 of the Pharmaceutical Affairs Law. In view of the characteristics of a drug, such a management is basically same in other countries as well. The reason why warranty of the quality is important for a drug as such is that the quality guarantees efficacy and safety of a drug. Conversely, with regard to a drug for which no quality is warranted, neither efficacy nor safety is guaranteed therefore whereby such a one is not competent as a drug.
In Japan, a material substance being used for the production of a drug and able to be an active ingredient of a drug is called a “drug substance” The same as in a drug, a drug substance is also necessary that its quality is warranted. That is because the quality of a drug depends upon the quality of a drug substance. Incidentally, according to Japanese laws and regulations related to pharmaceutical affairs, a drug substance is stipulated as a drug which is exclusively used for the manufacture of other drug and, in terms of the definition therefore, a drug substance is covered by a drug. However, in the present application, a medicament and a drug substance may be sometimes separately referred to for the sake of convenience and, in such a case, the meaning of a drug shall exclude a drug substance.
It is general that, when a drug or a drug substance is manufactured by a predetermined manufacturing method, that having a predetermined quality is manufactured. Accordingly, in order to maintain the quality of a drug or a drug substance, manufacture control is also important. For such a purpose, there has been stipulated “Ministerial Ordinance concerning the Standards for Manufacture Control and Quality Control of Drugs and Quasi-Drugs” in Japan. This ministerial ordinance is called GMP (abbreviation of Good Manufacturing Practice) in Japan as well. In GMP, “manufacture control” and “quality control” of drugs, etc. are stipulated. In “manufacture control”, there is adopted such a way of thinking that the quality is maintained by controlling the material preparation and the manufacturing steps from the initial to the final stages thereof. “Quality control” has been mainly conducted by means of confirmation of the tests and inspections conducted after the manufacture whether the manufactured drug or drug substance actually has predetermined quality standards. When the result of the tests and inspections does not satisfy the previously stipulated standards, then shipment, distribution, use, etc. of the drug and drug substance are not allowed. As such, the quality of drugs and drug substances are controlled by means of the manufacture control and the quality control.
An extract from inflamed skins of rabbits inoculated with vaccinia virus (hereinafter, it will be sometimes referred to as “the present extract”) is an extract containing a non-proteinous active substance extracted and separated from the inflamed skin tissues of rabbits by the inoculation of vaccinia virus. Although the present extract is liquid in an extracted state, it is also possible to make into a solid by means of drying.
As will be mentioned later, a preparation containing the present extract as an active ingredient (hereinafter, it will be sometimes called “the present preparation”) is very useful as a drug. Since the present extract is an active ingredient of the present preparation in that case, the present extract is a drug substance of the present preparation. In a specific product as the present preparation which is manufactured and distributed by the applicant, there is “a preparation containing an extract from inflamed skins of rabbits inoculated with vaccinia virus” (trade name: NEUROTROPIN [registered trademark]; hereinafter, it will be referred to as “NTP preparation”). In NTP preparation, there are injection (hereinafter, it will be referred to as “NTP injection”) and tablet (hereinafter, it will be referred to as “NTP tablet”) and both belong to an ethical drug. An extract from inflamed skins of rabbits inoculated with vaccinia virus (hereinafter, it will be referred to as “NTP extract”) which is an active ingredient of NTP preparation is a drug substance of NTP preparation. NTP extract is covered by the present extract while NTP preparation (NTP injection and NTP tablet) is covered by the present preparation.
Indications of NTP injection are “low back pain, cervicobrachial syndrome, symptomatic neuralgia, itchiness accompanied by skin diseases (eczema, dermatitis, urticaria), allergic rhinitis and sequelae of subacute myelo-optico-neuropathy (SMON) such as coldness, paresthesia and pain”. Indications of NTP tablet are “postherpetic neuralgia, low back pain, cervicobrachial syndrome, periarthritis scapulohumeralis and osteoarthritis”. NTP preparation has been created and developed as a drug by the applicant. NTP preparation has been appreciated for its excellent advantage for efficacy and safety, sold for many years and established a firm position in the Japanese pharmaceutical market. At present, NTP preparation is being exported to China and sold under a trade name of “/NEUROTROPIN”. Indications of NTP preparation in China are the same as those in Japan.
As such, the present preparation is very useful as a drug and the present extract is also very useful as a drug substance for the present preparation. However, as mentioned already, the present extract is extracted and separated from the inflamed skin tissues of rabbits by the inoculation of vaccinia virus. Therefore, the present extract contains quite a lot of substances (components) and the present preparation manufactured using the present extract also contains quite a lot of substances (components). Accordingly, it is a very important matter how to control the quality of the present extract and the present preparation in a stable one.
Many of drugs are the preparations containing one or two to three substances (components) at the largest as an active ingredient and, usually, such substances are the chemically synthesized compounds. Therefore, when the content of the compound(s) in said preparation is measured and a predetermined content is contained, the quality of said preparation in view of the content of the active ingredient(s) is guaranteed. However, the present extract is an extract from inflamed skin tissues of rabbits by the inoculation of vaccinia virus and contains quite many kinds of substances. It goes without saying that the present preparation where the present extract is an active ingredient also contains quite many kinds of substances. Thus, in the present extract and the present preparation, specific one or several kind(s) of substance(s) is/are not the active ingredient(s) as such whereby it is not possible to conduct a quality control as in the case of conventional drug where active ingredient(s) is/are specified as substance(s). Therefore, quantitative determination for active ingredient(s) of the present extract and the present preparation manufactured by the applicant or of NTP extract and NTP preparation is being carried out by such a method where the biological activity (titer) thereof is measured.
Said method is a biological test method where an analgesic coefficient is determined using SART-stressed (repeated cold stressed) animals which are chronic stressed animals showing a lowered pain threshold than normal animals (Folia Pharmaclogica Japonica, vol. 72, no. 5, pages 573 to 584, 1976). In accordance with the method in this literature, the analgesic coefficient is determined by conducting an analgesic test according to a Randall-Selitto method using SART-stressed (repeated cold stressed) animals which are chronic stressed animals showing a lowered pain threshold than normal animals. In this method, an analgesic effect is measured using a pressure weight as an index where the pressure stimulation is applied to the tail of mouse and the mouse shows an escape reaction. An analgesic coefficient is a value where the pressure weight measured after administration of a drug is divided by the value before the administration. In NTP extract and NTP preparation, the case where an analgesic coefficient showed more than a predetermined value defined by the applicant is judged to be positive for an analgesic effect and the rate of the numbers of animals judged to be positive is determined and used as an analgesic efficacy rate (%). This value is used and ED50 value is determined from the result upon measurement of standard preparation diluted to various concentrations. “Neurotropin Unit (NU)” which is a unit of biological activity (titer) using for NTP preparation by the applicant is defined that the activity of 1 mg of the present extract where the ED50 value is the dose of 100 mg/kg is 1 Neurotropin unit. ED50 value for each NTP preparation is measured and compared with that of the standard preparation whereupon an analgesic activity (active ingredient content) is quantitatively determined. Hereinafter in the present application, the word “unit” is used as a measure of the active ingredient content (titer) of the present extract and the present preparation and it is substantially in the same meaning as “Neurotropin Unit” used for NTP extract and NTP preparation.
In the meanwhile, it is stipulated that the present extract and the present preparation or NTP extract and NTP preparation manufactured by the applicant are to be subjected to the following plural identity tests in addition to the above-mentioned quantification of the analgesic activity and should conform to them. Thus, with regard to the present extract and the present preparation manufactured by the applicant, not only the above-mentioned biological activity (titer) is used for guaranteeing the appropriateness of the manufactured lots but also the following plural identity tests are carried out and adaptation thereto is used as a necessary condition for use and shipment of the present extract and the present preparation.                Identity test of amino acids by a liquid chromatographic method        Identity test of ultraviolet absorbing substances by Ultraviolet-visible Spectrophotometry        Identity test of phosphorus by a color reaction method        Identity test of nucleic acid base by a liquid chromatographic method        Identity test of inhibitory action for the production of kallikrein-like substance by an in vitro test method        
However, even when such tests are carried out, it is not always true that the amino acids, ultraviolet absorbing substances, phosphorus, nucleic acid bases, etc. which are objects of the tests are the crucial active ingredients of the present extract and the present preparation. Moreover, in those tests, the identity test for amino acids, ultraviolet absorbing substances, phosphorus and nucleic acid bases is a qualitative test which merely confirms the presence of amino acids, etc. which are objects of the tests and does not check how much amount is contained therein. Even under such circumstances however, those tests are still obligatory for the applicant in order to receive an approval for the manufacture of drugs from the government as a means for reducing the variations in the quality among the manufacturing lots and for guaranteeing the uniform quality in both of the present extract and the present preparation where the active ingredients are unidentified.
Generally speaking, it is advantageous for persons who manufacture an extract from living organisms such as animals and plants or a preparation containing said extract as an active ingredient if and when the standards to which said preparation should conform are small in numbers since time, labor and cost for the test and the inspection are saved and possibility where the manufactured product does not conform to the standard is low. However, in view of guaranteeing the quality of the above extract and preparation, it is desirable that the standard as such is stipulated more strictly. Under such circumstances, the applicant has extensively investigated the new appropriate standard to which the present extract and the present preparation manufactured by the applicant should conform whereupon the present invention has been achieved. Thus, the amount of sulfated tyrosine contained in the present extract and the present preparation is measured and, when the amount is within a predetermined range, it is treated that the present extract and the present preparation as such are appropriately manufactured or, in other words, their use and shipment are permitted. As a result, the variations among manufacturing lots of the present extract and the present preparation are further reduced and the quality thereof becomes more stable. Further, as a result, efficacy and safety of the present extract and the present preparation are guaranteed more strictly. If and when there is the present extract or the present preparation wherein the amount of sulfated tyrosine is out of the stipulated range, it is treated as an adulterated product (a substandard product) whereby it is possible to control the quality of the present extract and the present preparation in a more stable manner. Thus, it is now possible to stipulate an autonomous or a public standard concerning the amount of sulfated tyrosine contained in the present extract or the present preparation. In the meanwhile, the applicant has not stipulated a standard for the amount of sulfated tyrosine contained in an NTP extract and an NTP preparation manufactured up to now and has not conducted such an act that the amount is measured and that, after confirming the measured amount is within a predetermined range, the corresponding NTP extract and NTP preparation are used, shipped, etc.
As to the documents which disclose the present extract or the present preparation, Patent Documents 1 to 3 are available. Those documents disclose the content of amino acids and nucleic acid bases in the present extract or the present preparation. Further, with regard to the present extract or the present preparation, there is a disclosure for the content of silicons in Patent Document 4. However, in those Patent Documents 1 to 4, there is no disclosure at all how much a specific substance which is sulfated tyrosine is contained in the present extract or the present preparation. It further goes without saying that, in those documents, there is neither disclosure nor suggestion at all to adopt the content of sulfated tyrosine in the present extract or the present preparation as an index for the quality control of the present extract or the present preparation in more a stable manner.